DESCRIPTION: Type 2 diabetes mellitus is characterized by defects in both insulin action and insulin secretion. Disturbances in free fatty acid (FFA) metabolism also are a characteristic feature of type 2 diabetes mellitus and type 2 diabetic individuals demonstrate day-long increased plasma FFA levels. Interestingly, disturbances in FFA metabolism are observed in normal glucose tolerant, insulin-resistant, genetically predisposed individuals long before the onset of overt diabetes, and in these offspring, as well as in type 2 diabetic subjects, adipose tissue is resistant to the antilipolytic effects of insulin. This raises the interesting possibility that FFA act as metabolic messengers which, when released in increased amounts, can impair insulin action in muscle and liver, i.e. lipotoxicity. The PI proposes to examine the mechanisms of FFA-induced insulin resistance at the whole body, organ, biochemical, and molecular levels. Using the euglycemic insulin clamp in combination with indirect calorimetry, radioisotope techniques, vastus lateralis muscle biopsy, and forearm catheterization the PI shall examine the effect of elevated plasma FFA levels on the insulin signal transduction system, glucose transport and phosphorylation, glycolytic flux, glucose oxidation, and glycogen synthesis in healthy, type 2 diabetic, and IGT subjects, as well as in the offspring of two diabetic parents. The PI also will define the effect of chronically elevated plasma FFA levels on endogenous (primarily hepatic) glucose production, gluconeogenesis, and glycogenolysis. Abnormalities in muscle and hepatic glucose metabolism will be related to total body fat content, as well as to muscle, liver, and abdominal fat content. Lastly, the PI shall compare and contrast the effects of various FFA lowering agents and inhibitors of FFA oxidation on basal and insulin-mediated muscle and hepatic glucose metabolism, as well as on fat topography.